USP49 negatively regulates cellular antiviral responses via deconjugating K63-linked ubiquitination of MITA
文献类型：期刊论文
| 作者 | Ye, Liya1,2; Zhang, Qiang1,2; Liuyu, Tianzi1,2; Xu, Zhigao3; Zhang, Meng-Xin1,2; Luo, Min-Hua4; Zeng, Wen-Bo4; Zhu, Qiyun5; Lin, Dandan6; Zhong, Bo1,2 |
| 刊名 | PLOS PATHOGENS
 |
| 出版日期 | 2019-04-01 |
| 卷号 | 15期号:4页码:22 |
| ISSN号 | 1553-7366 |
| DOI | 10.1371/journal.ppat.1007680 |
| 英文摘要 | Mediator of IRF3 activation (MITA, also known as STING and ERIS) is an essential adaptor protein for cytoplasmic DNA-triggered signaling and involved in innate immune responses, autoimmunity and tumorigenesis. The activity of MITA is critically regulated by ubiquitination and deubiquitination. Here, we report that USP49 interacts with and deubiquitinates MITA after HSV-1 infection, thereby turning down cellular antiviral responses. Knockdown or knockout of USP49 potentiated HSV-1-, cytoplasmic DNA- or cGAMP-induced production of type I interferons (IFNs) and proinflammatory cytokines and impairs HSV-1 replication. Consistently, Usp49(-/-) mice exhibit resistance to lethal HSV-1 infection and attenuated HSV-1 replication compared to Usp49(+/+) mice. Mechanistically, USP49 removes K63-linked ubiquitin chains from MITA after HSV-1 infection which inhibits the aggregation of MITA and the subsequent recruitment of TBK1 to the signaling complex. These findings suggest a critical role of USP49 in terminating innate antiviral responses and provide insights into the complex regulatory mechanisms of MITA activation. Author summary Mediator of IRF3 activation (MITA) is an essential adaptor protein in mediating innate immune responses to DNA viruses. The activation of MITA requires K63-linked ubiquitination and oligomerization which promotes the recruitment of downstream kinases and phosphorylation of transcription factors to induce expression of downstream genes. In our study, we have discovered that the deubiquitinating enzyme USP49 interacts with and removes K63-linked polyubiquitin chains from MITA to downregulate antiviral signaling. USP49 deficiency results in enhanced production of antiviral cytokines and attenuated virus replication after HSV-1 infection in cells and in vivo. Our study thus reveals a negative feedback regulation of MITA activity and cellular antiviral responses. |
| 资助项目 | National Key Research and Development Program of China[2018YFC1004601] ; Natural Science Foundation of China[31601131] ; Natural Science Foundation of China[31671454] ; Natural Science Foundation of China[31622036] ; Natural Science Foundation of Hubei Province[2018CFA016] ; Health Commission of Hubei Province[WJ2018H0028] ; Wuhan University[2042017kf0199] ; Wuhan University[2042017kf0242] ; State Key Laboratory of Veterinary Etiological Biology[SKLVEB2017KFKT004] |
| WOS研究方向 | Microbiology ; Parasitology ; Virology |
| 语种 | 英语 |
| 出版者 | PUBLIC LIBRARY SCIENCE |
| WOS记录号 | WOS:000466742700022 |
| 源URL | [http://202.127.146.157/handle/2RYDP1HH/7263]  |
| 专题 | 中国科学院武汉植物园 |
| 通讯作者 | Lin, Dandan; Zhong, Bo |
| 作者单位 | 1.Wuhan Univ, Zhongnan Hosp, Med Res Inst, Dept Gastrointestinal Surg, Wuhan, Hubei, Peoples R China 2.Wuhan Univ, Coll Life Sci, Wuhan, Hubei, Peoples R China 3.Wuhan Univ, Zhongnan Hosp, Ctr Pathol & Mol Diagnost, Dept Pathol, Wuhan, Hubei, Peoples R China 4.Chinese Acad Sci, Wuhan Inst Virol, CAS Ctr Excellence Brain Sci & Intelligence Techn, State Key Lab Virol, Wuhan, Hubei, Peoples R China 5.Chinese Acad Agr Sci, Lanzhou Vet Res Inst, State Key Lab Vet Etiol Biol, Lanzhou, Gansu, Peoples R China 6.Wuhan Univ, Renmin Hosp, Canc Ctr, Wuhan, Hubei, Peoples R China |
| 推荐引用方式 GB/T 7714 | Ye, Liya,Zhang, Qiang,Liuyu, Tianzi,et al. USP49 negatively regulates cellular antiviral responses via deconjugating K63-linked ubiquitination of MITA[J]. PLOS PATHOGENS,2019,15(4):22. |
| APA | Ye, Liya.,Zhang, Qiang.,Liuyu, Tianzi.,Xu, Zhigao.,Zhang, Meng-Xin.,...&Zhong, Bo.(2019).USP49 negatively regulates cellular antiviral responses via deconjugating K63-linked ubiquitination of MITA.PLOS PATHOGENS,15(4),22. |
| MLA | Ye, Liya,et al."USP49 negatively regulates cellular antiviral responses via deconjugating K63-linked ubiquitination of MITA".PLOS PATHOGENS 15.4(2019):22. |
入库方式： OAI收割
来源：武汉植物园
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